(1) Field of the Invention
This invention relates to an improved general process for producing arylglyoxal arylimine intermediates by the oxidation of aryl methylketones which are useful in carbapenem antibiotic synthesis.
(2) Brief Description of Disclosures in the Art
Carbapenem antibiotics, particularly thienamycin and imipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) are well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections.
Processes for synthesis of these type antibacterial agents are well known in the art as witness the following patents issued inter alia to Merck & Co.; U.S. Pat. Nos. 4,543,257, 4,234,596 and 4,232,030.
In order to develop, faster, less expensive and better methods for their production, research is continually being carried out in this area. One focus in this field has been on different modes for the synthesis of the starting azetidinone intermediates.
For example, the one-step cycloaddition of an imine and a ketene to product azetidinones is well known in the art, e.g. H. Staudinger and S. Jologin, Chem. Ber., 1911, 44, p. 373.
Since the discovery of (3R,4R)-3-[(1R)-1-hydroxyethyl]-4-acetoxyazetidin-2-one (1) (see Scheme I) as a key intermediate for the synthesis of the carbapenems thienamycin and methyl thienamycin an intensitve effort has been directed towards the development of a selective and cost-efficient synthesis of 1 or its 4-aroyl precursor 6. (See: Reider, P. J.; Grabowski, E. J. J.; Tetrahedron Lett. 1982, 2293; Ito, Y.; Terashima, S.; Tetrahedron Lett. 1987, 6625; Fuentes, L. M., Shinkai, I., Salzmann, T., J. Am. Chem. Soc. 1986, 108, 4673; Ito, Y., Kawabata, T., Terashima S., Tetrahedron Lett. 1986, 5751; Hart, D. J., Ha, D. C., Tetrahedron Lett. 1985, 5493.) It has recently been demonstrated that 4-aroyl-2-azetidinone 6 is readily available via cycloaddition of 3(S)-triisopropylsilyloxybutyryl chloride 4 with p-anisidine 1,2-iminoketone 5 in the presence of a tertiary amine base such as triethylamine. (See: Alcaide, B., Dominquez, G., Parreno, V., Plumet, J., Heterocycles, 1986, 24, 6). ##STR1## The 1,2-iminoketone 5 was previously prepared from phenylglyoxal monohydrate and p-anisidine via standard methodology (see Alcaide et al. supra). However, due to the prohibitively high cost of phenylglyoxal monohydrate people in the art are interested in the development of an alternative, more cost-effective methodology for its synthesis that would be applicable for large scale production of imine 5.
It has been known for some time that active carbonyl compounds are oxidized to 1,2 dicarbonyl compounds by dimethyl sulfoxide in the presence of hydrogen halides. For example, Schipper and co-workers have described the use of aqueous HBr in dimethyl sulfoxide for the oxidation of 1,3-diketones to 1,2,3-triketones. (See Schipper, E., Cinnamon, M., Rascher, L., Chiang, Y. H., Oroshnik, W., Tetrahedron Lett. 1968, 6201.) However, the yield for the oxidation of acetophenone to phenylglyoxal was reported to be only 10%. Similarly, Furukawa, et al. (see Furukawa, N., Akasaka, T., Aida, T., Oae, S., J. Chem. Soc. Perkin I. 1977, 372) employed iodine, dimethyl sulfoxide, and sulfuric acid for analogous oxidations of several active methylene systems; however, only traces of phenylglyoxal were obtained when acetophenone was used as the substrate.